Bio


Dr. Bharadwaj is fellowship-trained in blood and marrow transplantation, cellular therapy, hematology, and oncology. She is an instructor in the Stanford School of Medicine Department of Medicine, Division of Blood & Marrow Transplantation and Cellular Therapy.

Dr. Bharadwaj focuses her expertise on diagnosing and treating cancer in blood and bone marrow. For each patient, she develops a personalized, comprehensive, and compassionate care plan. In her diverse experience as a physician and scientist, she has served as an internal medicine doctor, hospitalist, hematologist, oncologist, and blood and marrow transplantation specialist. Dr. Bharadwaj has a degree in clinical research and is currently conducting clinical trials in transplant and cellular therapy.

She has participated in research studies of advances in therapy for chronic lymphocytic leukemia, melanoma, and breast cancer. She has co-authored articles published in Leukemia and Lymphoma and elsewhere. Topics include advances in cell transplantation. She also co-wrote the chapter on genome-driven personalized cancer therapy in the book Precision Medicine in Oncology.

Dr. Bharadwaj has made presentations at meetings of the American Society of Hematology, American Society of Clinical Oncology, and other associations.
Subjects include racial, demographic, and socioeconomic disparities in the treatment of patients with acute myeloid leukemia.

Dr. Bharadwaj is a member of the American Society for Transplantation and Cellular Therapy, American Society of Hematology, and American Society of Clinical Oncology.

Clinical Focus


  • Cancer > Blood and Marrow Transplant
  • Cancer > Hematology > Leukemia - Acute and Chronic
  • Cancer > Lymphoma
  • Hematology
  • Leukemia
  • Lymphoma

Academic Appointments


Honors & Awards


  • ASTCT Clinical Research Training Course Scholar, ASTCT (2022)
  • Organizational Excellence Award, South Zone Pharmacology Conference, Mangalore, India

Professional Education


  • Board Certification: American Board of Internal Medicine, Hematology (2021)
  • Board Certification: American Board of Internal Medicine, Internal Medicine (2021)
  • Fellowship: Stanford University Bone Marrow Transplant Fellowship (2021) CA
  • Fellowship: Cook County Health Hematology Oncology Fellowship (2020) IL
  • Residency: John H Stroger Jr Hospital of Cook County Internal Medicine Residency (2013) IL
  • Internship: University of Illinois College of Medicine at Peoria (2011) IL
  • Medical Education: Kasturba Medical College Mangalore (2006) India

Clinical Trials


  • Safety of Myeloablative Conditioning, Orca-T, and Allogeneic, Donor-Derived CD19/CD22-CAR (Chimeric Antigen Receptor) T Cells in Adults With B-cell Acute Lymphoblastic Leukemia (ALL) Recruiting

    To assess the safety of administering allogenic, donor-derived CD19/CD22-CAR T cells that meet established release specifications in adults with B-cell ALL following a myeloablative conditioning regimen and Orca-T to determine if this will augment graft versus leukemia without increasing acute GVHD or graft failure.

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All Publications


  • A 17-Year Experience of a Large Dedicated Fellowship in Blood and Marrow Transplantation and Cellular Therapy: A Blueprint for Modern Day Training Program. Journal of cancer education : the official journal of the American Association for Cancer Education Bharadwaj, S., Lowsky, R., Mikkilineni, L., Smith, M., Weng, W. K. 2024

    Abstract

    The field of allogeneic blood and marrow transplantation-cellular therapy (BMT-CT) has evolved through incremental advances. Engineered donor grafts, gene editing and chimeric antigen receptor T-cells are all standard clinical practice. Consequently, the scientific knowledge and complexity of clinical skills needed for next generation of BMT-CT physicians have increased. We report a 17-year experience of arguably the largest 12-month BMT-CT clinical fellowship program in the USA. Seventy-three (73) trainees were accepted and 2 cohorts that reflected different time periods (2007-1016 and 2017-2024, inclusive) and different core training curriculum were compared. The cohorts were equivalent in terms of demographics; notably, most (70%) had graduated from international medical schools and trained in the US on a non-immigrant J1 visa. In 2015, we introduced a structured mentoring program to address the desire of trainees for experience with scholarly activities. There was a high rate of successful academic careers with a trend toward a higher likelihood of academic retention following structured mentoring (70% vs 89%). In this report, we included our detailed core curriculum and highlight potential future changes as a blueprint for modern day programs to ensure that graduate "transplant docs" can continue to contribute at the highest academic level.

    View details for DOI 10.1007/s13187-024-02545-3

    View details for PubMedID 39604772

    View details for PubMedCentralID 9947862

  • Belumosudil combination therapy for chronic graft-versus-host-disease in real-world clinical practice. Bone marrow transplantation Chin, M. M., Tamaresis, J. S., Johnston, L. J., Lowsky, R., Meyer, E., Muffly, L., Shiraz, P., Frank, M. J., Rezvani, A. R., Bharadwaj, S., Weng, W. K., Shizuru, J. A., Arai, S. 2024

    View details for DOI 10.1038/s41409-024-02476-z

    View details for PubMedID 39558138

    View details for PubMedCentralID 9355804

  • Real-World Outcomes of Lisocabtagene Maraleucel (liso-cel) in Patients With Richter Transformation (RT) From the Center for International Blood and Marrow Transplant Research (CIBMTR) Mirza, A., Winter, A., Bharadwaj, S., Herrera, A. F., Iragavarapu, C., Palomba, M., Patel, S. S., Gharibo, M., Bernasconi, D., Krimmel, T., Liu, F., Roy, D., Pasquini, M. C. CIG MEDIA GROUP, LP. 2024: S347-S348
  • ALPHA2: A Phase 1b Study Evaluating the CD19 Allogeneic CAR T Cell Product Cemacabtagene Ansegedleucel (Cema-Cel) in Patients With Relapsed/ Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Miklos, D., Bharadwaj, S., Holmes, H., Oluwole, O., Jallouk, A., Neelapu, S., Jain, N., Nath, R., Munoz, J., Bryan, L., De Vos, S., Eradat, H., Patel, R., Tees, M., Tsai, S., Cahill, K., Sohl, M., Shouse, G., Stevens, D., Fisher, P., Feng, A., Severyn, C., Le Gall, J., Locke, F., Pinilla, J. CIG MEDIA GROUP, LP. 2024: S604
  • CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study. Lancet (London, England) Frank, M. J., Baird, J. H., Kramer, A. M., Srinagesh, H. K., Patel, S., Brown, A. K., Oak, J. S., Younes, S. F., Natkunam, Y., Hamilton, M. P., Su, Y. J., Agarwal, N., Chinnasamy, H., Egeler, E., Mavroukakis, S., Feldman, S. A., Sahaf, B., Mackall, C. L., Muffly, L., Miklos, D. B. 2024

    Abstract

    Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study.In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment.From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome.This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach.National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

    View details for DOI 10.1016/S0140-6736(24)00746-3

    View details for PubMedID 38996463

  • A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia. Blood Srinagesh, H. K., Jackson, C., Shiraz, P., Jeyakumar, N., Hamilton, M. P., Egeler, E., Mavroukakis, S., Kuo, A., Cancilla, J., Sahaf, B., Agarwal, N., Kanegai, A. M., Kramer, A. M., Arai, S., Bharadwaj, S., Dahiya, S., Hosoya, H., Johnston, L. J., Kennedy, V. E., Liedtke, M., Lowsky, R., Mikkilineni, L., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J. A., Smith, M., Weng, W. K., Feldman, S. A., Frank, M. J., Lee, Z., Tagliaferri, M., Marcondes, A. M., Miklos, D. B., Mackall, C. L., Muffly, L. 2024

    Abstract

    While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

    View details for DOI 10.1182/blood.2024024952

    View details for PubMedID 38968138

  • Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma. Journal for immunotherapy of cancer Bharadwaj, S., Lau, E., Hamilton, M. P., Goyal, A., Srinagesh, H., Jensen, A., Lee, D., Mallampet, J., Elkordy, S., Syal, S., Patil, S., Latchford, T., Sahaf, B., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R., Rezvani, A. R., Shizuru, J., Meyer, E. H., Shiraz, P., Mikkilineni, L., Weng, W. K., Smith, M., Sidana, S., Muffly, L., Maecker, H. T., Frank, M. J., Mackall, C., Miklos, D., Dahiya, S. 2024; 12 (7)

    Abstract

    Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy.84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC.Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts.Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.

    View details for DOI 10.1136/jitc-2024-008975

    View details for PubMedID 38955420

  • CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity. Blood advances Hamilton, M. P., Craig, E., Gentille Sanchez, C., Mina, A., Tamaresis, J., Kirmani, N., Ehlinger, Z., Syal, S., Good, Z., Sworder, B., Schroers-Martin, J., Lu, Y., Muffly, L., Negrin, R. S., Arai, S., Lowsky, R., Meyer, E., Rezvani, A. R., Shizuru, J. A., Weng, W. K., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Kurtz, D. M., Mackall, C. L., Tibshirani, R., Alizadeh, A. A., Frank, M. J., Miklos, D. B. 2024

    Abstract

    Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas. CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell (MCL), follicular (FL), and large B-cell lymphoma (LBCL) over the course of five years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL compared to other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required four-fold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and the requirement for granulocyte colony stimulating factor (GCSF) after day 14 post-infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

    View details for DOI 10.1182/bloodadvances.2024012637

    View details for PubMedID 38498731

  • CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results. Leukemia Schultz, L. M., Jeyakumar, N., Kramer, A. M., Sahaf, B., Srinagesh, H., Shiraz, P., Agarwal, N., Hamilton, M., Erickson, C., Jacobs, A., Moon, J., Baggott, C., Arai, S., Bharadwaj, S., Johnston, L. J., Liedtke, M., Lowsky, R., Meyer, E., Negrin, R., Rezvani, A., Shizuru, J., Sidana, S., Egeler, E., Mavroukakis, S., Tunuguntla, R., Gkitsas-Long, N., Retherford, A., Brown, A. K., Gramstrap-Petersen, A. L., Ibañez, R. M., Feldman, S. A., Miklos, D. B., Mackall, C. L., Davis, K. L., Frank, M., Ramakrishna, S., Muffly, L. 2024

    Abstract

    Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

    View details for DOI 10.1038/s41375-024-02220-y

    View details for PubMedID 38491306

    View details for PubMedCentralID 4993814

  • Lisocabtagene maraleucel for treatment of relapsed and refractory primary mediastinal large B-cell lymphoma in an adolescent patient. EJHaem Lee, D., Goyal, A., Wang, W. L., Ananth, S., Lau, E., Binkley, M. S., Bharadwaj, S., Dahiya, S. 2024; 5 (1): 153-156

    Abstract

    The safety and efficacy of CAR T-cell therapy are unknown in pediatric and adolescent patients with relapsed or refractory primary mediastinal large B-cell lymphoma (R/R PMBCL) which is associated with dismal prognosis. Here, we present a case report of a 16-year-old patient with R/R PMBCL treated with lisocabtagene maraleucel including correlative studies. Patient achieved complete response at 6 months without cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. She only experienced mild cytopenias, requiring filgrastim once. This report highlights the safety and efficacy of lisocabtagene maraleucel in this population, warranting prospective studies to improve clinical outcomes.

    View details for DOI 10.1002/jha2.859

    View details for PubMedID 38406546

  • Clinical Features of Neurotoxicity Following CD19 CAR T-cell Therapy in Mantle Cell Lymphoma. Blood advances Nie, E. H., Su, Y. J., Baird, J. H., Agarwal, N., Bharadwaj, S., Weng, W. K., Smith, M., Dahiya, S., Han, M. H., Dunn, J. E., Kipp, L. B., Miklos, D. B., Scott, B. J., Frank, M. J. 2024

    Abstract

    CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development following CD19 CAR T-cell therapy in patients with MCL. All patients (n = 26) who received standard of care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (≥ grade 3) ICANS. All ICANS patients had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. 92% of EEGs revealed interictal changes; no patients experienced frank seizures due to ICANS. 86% of severe ICANS patients with post-infusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of post-infusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in severe ICANS patients, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

    View details for DOI 10.1182/bloodadvances.2023011896

    View details for PubMedID 38295285

  • TIGIT is Frequently Expressed in the Tumor Microenvironment of Select Lymphomas: Implications for Targeted Therapy. The American journal of surgical pathology Libert, D., Zhao, S., Younes, S., Mosquera, A. P., Bharadwaj, S., Ferreira, C., Natkunam, Y. 2023

    Abstract

    Immune checkpoint inhibitors against Programmed Cell Death Protein 1/Programmed Cell (PD-1/PD-L1) and CTLA-4/B7 axes have had limited success in hematologic malignancies, requiring the need to explore alternative targets such as T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 to improve durable clinical responses. We undertook this study to investigate the expression profile of TIGIT such that the potential efficacy of TIGIT blockade could be mapped among lymphoma subtypes. We validated an immunohistochemical assay for TIGIT and evaluated its expression in lymphoma and tumor microenvironment (TME) cells in 661 lymphoma/leukemia biopsies. Multiplex immunofluorescence was used for correlation with normal TME cell subsets. Tumor or TME TIGIT-positivity was defined as moderate to strong membrane staining in at least 10% of tumor or TME cells, respectively. TME TIGIT expression was correlated with overall survival and progression-free survival and comparison with PD-L1 expression. In most cases, lymphoma cells were TIGIT-negative except for angioimmunoblastic and peripheral T-cell lymphomas, which showed 91% and 47% positivity, respectively. A high proportion of small B-cell lymphoma and anaplastic large cell lymphoma cases had TIGIT-positive TME cells. Chronic lymphocytic leukemia/small lymphocytic lymphoma patients with TIGIT-negative TME cells showed significantly shorter overall survival (P=0.04). No other statistically significant differences were found. When TIGIT was expressed in TME cells, there were a comparable number of TIGIT-positive only and dual TIGIT/PD-L1 positive cases except for more TIGIT-positive only cases in CLL/SLL. TIGIT expression shows distinctive profiles among lymphoma subtypes. Chronic lymphocytic leukemia/small lymphocytic lymphoma and anaplastic large cell lymphoma demonstrated high TME TIGIT expression compared with PD-L1, with a high proportion of dual TIGIT and PD-L1-positivity. Our results are likely to contribute to the design and correlative study of therapeutic response in clinical trials targeting TIGIT alone or in combination with PD1/PDL1.

    View details for DOI 10.1097/PAS.0000000000002168

    View details for PubMedID 38148663

  • Single Center Randomized Trial of T-reg graft alone versus T-reg graft Plus Tacrolimus for the Prevention of Acute GVHD. Blood advances Bader, C. S., Pavlova, A., Lowsky, R., Muffly, L., Shiraz, P., Arai, S., Johnston, L. J., Rezvani, A. R., Weng, W. K., Miklos, D. B., Frank, M. J., Tamaresis, J. S., Agrawal, V., Bharadwaj, S., Sidana, S., Shizuru, J. A., Fernhoff, N. B., Putnam, A., Killian, S., Xie, B. J., Negrin, R. S., Meyer, E. 2023

    Abstract

    Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies for which graft-versus-host disease (GVHD) remains a major complication. The use of donor T regulatory cells (Tregs) to prevent GVHD appears promising, including in our previous evaluation of an engineered graft product (T-reg graft) consisting of the timed, sequential infusion of CD34+ hematopoietic stem cells and high-purity Tregs followed by conventional T cells. However, whether immunosuppressive prophylaxis can be removed from this protocol remains unclear. We report the results of the first stage of an open-label single-center phase 2 study (NCT01660607) investigating T-reg graft in myeloablative HCT of HLA-matched and 9/10 matched recipients. Twenty-four patients were randomized to receive T-reg graft alone (n=12) or T-reg graft plus single-agent GVHD prophylaxis (n=12) to determine if T-reg graft alone was non-inferior in preventing acute GVHD. All patients developed full donor myeloid chimerism. Patients with T-reg graft alone versus with prophylaxis had an incidence of grade II-IV acute GVHD of 58% versus 8% (p=0.005) and grade III-IV of 17% versus 0% (p=0.149), respectively. The incidence of moderate to severe chronic GVHD was 28% in the T-reg graft alone arm versus 0% with prophylaxis (p=0.056). Among patients with T-reg graft and prophylaxis, CD4+ T cell:Treg ratios were reduced after transplantation, gene-expression profiles showed reduced CD4+ proliferation, and the achievement of full donor T cell chimerism was delayed. This study indicates that T-reg graft with single-agent tacrolimus is preferred to T-reg graft alone for the prevention of acute GVHD. Clinical Trial #: NCT01660607.

    View details for DOI 10.1182/bloodadvances.2023011625

    View details for PubMedID 38091578

  • CAR19 Therapy Drives Expansion of Clonal Hematopoiesis and Associated Cytopenias Hamilton, M. P., Sworder, B. J., Alig, S. K., Good, Z., Boegeholz, J., Schroers-Martin, J., Tamaresis, J., Esfahani, M., Lu, Y., Olsen, M., Liu, C., Ehlinger, Z., Desai, M., Liu-Fei, F., Muffly, L. S., Negrin, R. S., Arai, S., Johnston, L., Lowsky, R., Meyer, E. H., Rezvani, A. R., Shizuru, J., Weng, W., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Diehn, M., Frank, M. J., Mackall, C. L., Kurtz, D. M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023
  • Second-Line Chimeric Antigen Receptor T Cell Therapy (CAR-T) As Standard of Care for Relapsed-Refractory Large B-Cell Lymphoma (LBCL) Dahiya, S., Spiegel, J. Y., Lee, D., Mohammed, T., Lutfi, F., Goyal, A., Hana, C., Chavez, J. C., Ionescu, F., Frank, M. J., Bharadwaj, S., Sandoval-Sus, J., Beitinjaneh, A. M., Lekakis, L. J., McGuirk, J. P., Locke, F. L., Miklos, D. B., Jain, M. D. AMER SOC HEMATOLOGY. 2023
  • CD22 CAR T Cell-Related IEC-HS Is Associated with an IFN-. Cytokine Signature Srinagesh, H., Baird, J. H., Agarwal, N., Su, Y., Kramer, A., Reschke, A., Jeyakumar, N., Bharadwaj, S., Schultz, L., Ramakrishna, S., Davis, K. L., Sahaf, B., Feldman, S., Mackall, C. L., Miklos, D. B., Muffly, L. S., Frank, M. J. AMER SOC HEMATOLOGY. 2023
  • Impact of Obesity on Efficacy, Safety, and Expansion Kinetics of Chimeric Antigen Receptor-T (CAR T) Therapy in Patients with Relapsed or Refractory Large B Cell Lymphoma (LBCL) Goyal, A., Bharadwaj, S., Lee, D., Lau, E., Hamilton, M. P., Jensen, A., Sahaf, B., Syal, S., Patil, S., Cancilla, J. E., Latchford, T., Weng, W., Smith, M., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023
  • Long-Term Efficacy and Immune Reconstitution with Bendamustine As a Lymphodepleting Agent for Axicabtagene Ciloleucel (Axi-Cel) in Patients with Refractory or Relapsed Large B-Cell Lymphoma (LBCL) Bharadwaj, S., Lau, E., Goyal, A., Hamilton, M. P., Srinagesh, H., Jensen, A., Syal, S., Mallampet, J., Latchford, T., Sahaf, B., Weng, W., Smith, M., Maecker, H. T., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023
  • Post-CAR-T Minimal Residual Disease (MRD) Monitoring in Mantle Cell Lymphoma Enables Early Relapse Detection Ananth, S., Su, Y., Hamilton, M. P., Agarwal, N., Weng, W., Dahiya, S., Bharadwaj, S., Mallampet, J., Smith, M., Kong, K., Twoy, A., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2023
  • Analysis of PET-CT Derived Radiomic Biomarkers with Efficacy, Safety, and Expansion of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL) Bharadwaj, S., Lau, E., Hashmi, A., Hamilton, M. P., Jensen, A., Goyal, A., Marar, M., Lee, C., Ananth, S., Sahaf, B., Mallampet, J., Ehlinger, Z., Syal, S., Patil, S., Guo, H., Smith, M., Weng, W., Frank, M. J., Binkley, M. S., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023
  • Phase 1 Trial Results for Patients with Advanced Hematologic Malignancies Undergoing Reduced Intensity Allogeneic HCT with Orca-T Donor Cell Therapy Product and Single Agent Tacrolimus Villar-Prados, A., Meyer, E. H., Sutherland, K., Negrin, R. S., Arai, S., Frank, M. J., Johnston, L., Lowsky, R., Miklos, D. B., Muffly, L. S., Dahiya, S., Rezvani, A. R., Sidana, S., Shiraz, P., Shizuru, J., Weng, W., Smith, M., Bharadwaj, S., Tamaresis, J., Pavlova, A., McClellan, S. AMER SOC HEMATOLOGY. 2023
  • Bendamustine vs. fludarabine/cyclophosphamide lymphodepletion prior to BCMA CAR-T cell therapy in multiple myeloma. Blood cancer journal Sidana, S., Hosoya, H., Jensen, A., Liu, L., Goyal, A., Hovanky, V., Sahaf, B., Bharadwaj, S., Latchford, T., Arai, S., Leahy, S., Mei, M., Budde, L. E., Muffly, L. S., Frank, M. J., Dahiya, S., Htut, M., Miklos, D., Janakiram, M. 2023; 13 (1): 158

    View details for DOI 10.1038/s41408-023-00929-0

    View details for PubMedID 37833271

    View details for PubMedCentralID PMC10576036

  • Idecabtagene vicleucel chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma with renal impairment. Haematologica Sidana, S., Peres, L. C., Hashmi, H., Hosoya, H., Ferreri, C., Khouri, J., Dima, D., Atrash, S., Voorhees, P., Simmons, G., Sborov, D. W., Kalariya, N., Hovanky, V., Bharadwaj, S., Miklos, D., Wagner, C., Kocoglu, M. H., Kaur, G., Davis, J. A., Midha, S., Janakiram, M., Freeman, C., Alsina, M., Locke, F., Gonzalez, R., Lin, Y., McGuirk, J., Afrough, A., Shune, L., Patel, K. K., Hansen, D. K. 2023

    Abstract

    We evaluated patients with relapsed multiple myeloma with renal impairment (RI treated with standard of care ide-cel, as outcomes with CAR-T therapy are unknown in this population. RI was defined as creatinine clearance (CrCl < 50 ml/min. CrCl of < 30 ml/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13% patients with RI, including 11 patients severe RI (dialysis, n=1. Patients with RI were older, more likely to be female and had higher likelihood of having R-ISS stage 3 disease. Rates and severity of CRS (89% vs 84%, grade ≥ 3: 7% vs 2% and ICANS (23% vs 20% were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term ≥ grade 3 cytopenias, although cytopenias were similar by 3 months following CAR-T. Renal function did not worsen after CAR-T in patients with RI. Response rates (93% vs 82% and survival outcomes (median PFS: 9 vs 8 months, p=0.26 were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.

    View details for DOI 10.3324/haematol.2023.283940

    View details for PubMedID 37731379

  • Detection of Aberrant CD58 Expression in a Wide Spectrum of Lymphoma Subtypes: Implications for Treatment Resistance. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Younes, S., Zhao, S., Bharadwaj, S., Mosquera, A. P., Libert, D., Johnsrud, A., Majzner, R. G., Miklos, D. B., Frank, M. J., Natkunam, Y. 2023: 100256

    Abstract

    CD58 or lymphocyte function-associated antigen-3, is a ligand for CD2 receptors on T- and NK-cells and is required for their activation and target cell killing. We recently showed a trend towards higher frequency of CD58 aberrations in patients with diffuse large B-cell lymphoma (DLBCL) who progressed on CAR-T cell treatment compared to those who responded. Given that CD58 status may be an important measure of T-cell mediated therapy failure, we developed CD58 immunohistochemical assay and evaluated CD58 status in 748 lymphomas. Our results show that CD58 protein expression is downregulated in a significant proportion of all subtypes of B- T- and NK-cell lymphomas. CD58 loss is significantly related to poor prognostic indicators in DLBCL and to ALK and DUSP22 rearrangements in anaplastic large cell lymphoma. However, it is not associated with overall or progression free survival in any of the lymphoma subtypes. As eligibility for CAR-T therapy is being extended to a broader spectrum of lymphomas, mechanisms of resistance, such as target downregulation and CD58 loss, may limit therapeutic success. CD58 status is therefore an important biomarker in lymphoma patients who may benefit from next generation T-cell mediated therapies or other novel approaches that mitigate immune escape.

    View details for DOI 10.1016/j.modpat.2023.100256

    View details for PubMedID 37391168

  • Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19 CAR T-cell therapy for mantle cell lymphoma. Journal of neuropathology and experimental neurology Nie, E. H., Ahmadian, S. S., Bharadwaj, S. N., Acosta-Alvarez, L., Threlkeld, Z. D., Frank, M. J., Miklos, D. B., Monje, M., Scott, B. J., Vogel, H. 2023

    Abstract

    Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.

    View details for DOI 10.1093/jnen/nlac121

    View details for PubMedID 36592076

  • Idecabtagene Vicleucel Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma with Renal Insufficiency: Real World Experience Sidana, S., Peres, L. C., Hashmi, H., Hosoya, H., Ferreri, C. J., Atrash, S., Khouri, J., Voorhees, P. M., Dima, D., Simmons, G., Kalariya, N., Hovanky, V., Bharadwaj, S., Arai, S., Miklos, D. B., Wagner, C. B., Davis, J., Sborov, D. W., Nishihori, T., Alsina, M., Locke, F. L., Gonzalez, R., Kocoglu, M., Sannareddy, A., Afrough, A., McGuirk, J. P., Shune, L. O., Patel, K., Hansen, D. K. AMER SOC HEMATOLOGY. 2022: 10377-10379
  • Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects Hamilton, M. P., Liu-Fei, F. C., Alig, S. K., Tamaresis, J., Esfahani, M., Good, Z., Sworder, B., Schroers-Martin, J., Liu, C., Severinsen, F., Hanson, P. J., Lu, Y., Lowsky, R., Negrin, R. S., Meyer, E. H., Smith, M., Bharadwaj, S., Shizuru, J. A., Sidana, S., Shiraz, P., Rezvani, A. R., Johnston, L. J., Weng, W., Arai, S., Muffly, L., Dahiya, S., Diehn, M., Kurtz, D. M., Sahaf, B., Mackall, C. L., Frank, M. J., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 7545-7547
  • The Development of Carhlh after Axicabtagene Ciloleucel Is Associated with Poor Outcomes Philip, S., Srinagesh, H. K., Hamilton, M. P., Gentille, C., Mina, A., Arai, S., Johnston, L. J., Lowsky, R., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Bharadwaj, S., Dahiya, S., Muffly, L., Smith, M., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2022: 12775-12777
  • Analysis of Bendamustine Lymphodepletion, CD19 CART Expansion, Safety and Efficacy in Patients with Rel/Ref NonHodgkin Lymphoma Bharadwaj, S., Hamilton, M. P., Sahaf, B., Tamaresis, J., Patil, S., Hanson, P. J., Latchford, T., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Meyer, E. H., Shiraz, P., Sidana, S., Smith, M., Weng, W., Muffly, L., Mackall, C. L., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2022: 10371-10373
  • Belumosudil Combination Therapy in Refractory Chronic Graft-Versus-Host Disease Chin, M., Shizuru, J. A., Muffly, L., Shiraz, P., Johnston, L. J., Lowsky, R., Rezvani, A. R., Frank, M. J., Bharadwaj, S., Weng, W., Negrin, R. S., Miklos, D. B., Arai, S. AMER SOC HEMATOLOGY. 2022: 4788-4789
  • Outcomes for Acute Myeloid Leukemia Relapse after Allogeneic Hematopoietic Cell Transplantation Remain Poor in the Modern Era Philip, S., Lowsky, R., Johnston, L. J., Arai, S., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Bharadwaj, S., Frank, M. J., Miklos, D. B., Smith, M., Muffly, L., Agrawal, V. AMER SOC HEMATOLOGY. 2022: 4825-4827
  • Geriatrics assessment in older adults referred for hematopoietic cell transplantation. Journal of the American Geriatrics Society Sossenheimer, P. H., Bharadwaj, S., Johnston, L., Periyakoil, V. S. 2022

    View details for DOI 10.1111/jgs.17929

    View details for PubMedID 35708096

  • Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with CD19 CAR T-cell lymphoma therapy Nie, E., Ahmadian, S., Bharadwaj, S., Acosta-Alvarez, L., Threlkeld, Z., Frank, M., Miklos, D., Born, D., Scott, B., Monje, M., Vogel, H. OXFORD UNIV PRESS INC. 2022: 464
  • Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia in the Modern Era. Transplantation and cellular therapy Liang, E. C., Craig, J., Torelli, S., Cunanan, K., Iglesias, M., Arai, S., Frank, M. J., Johnston, L., Lowsky, R., Meyer, E. H., Miklos, D. B., Negrin, R., Rezvani, A., Shiraz, P., Shizuru, J., Sidana, S., Weng, W. K., Bharadwaj, S., Muffly, L. 2022

    Abstract

    Allogeneic hematopoietic cell transplantation (HCT) remains an important treatment for adults with acute lymphoblastic leukemia (ALL). We hypothesized that advances in ALL and transplantation have resulted in improved HCT outcomes in recent years.To evaluate the characteristics and outcomes of adult ALL patients undergoing allogeneic HCT over the last decade.Patients with ALL aged ≥18 years old who underwent allogeneic HCT at Stanford University between 2008 and 2019 were included in this study. Patients were divided into two Eras based on year of HCT: 2008-2013 (Earlier Era) and 2014-2019 (Later Era).A total of 285 patients were included: 119 patients underwent HCT in the Earlier Era and 166 in the Later Era. Patients transplanted in the Later Era were more likely to be Hispanic (38% vs. 21%) and to have HCT-Comorbidity Index of ≥ 3 (31% vs. 18%). Donor source for HCT also differed with an increase in the use of HLA-mismatched donor sources (38% vs. 24%), notably umbilical cord blood (UCB) in the Later Era (16% vs. 0%). Patients in the Later Era were less likely to undergo transplant with active disease (4% vs.16%); pre-HCT rates of measurable residual disease (MRD) were similar across the Eras (38% vs. 40%). In unadjusted analyses, overall survival (OS) improved across Eras, with 2-year estimates for the Later and Earlier Eras of 73% (95% CI, 66%-80%) vs. 55% (95% CI, 46%-64%), respectively. Multivariable analysis confirmed the association between Later Era and OS (HR = 0.52, 95% CI, 0.34-0.78). Finally, among patients relapsing after HCT (25% in Later Era and 33% in Earlier Era), the utilization of novel immunotherapies increased in the Later Era (44% vs. 3%), as did the median OS following post-HCT relapse (16 months vs. 8 months, p < 0.001).OS following HCT for adult ALL has improved in recent years. This is due, in part, to a significant improvement in the ability to effectively salvage adults with ALL relapsing after HCT.

    View details for DOI 10.1016/j.jtct.2022.05.010

    View details for PubMedID 35584783

  • Detection of Aberrant CD58 Expression in a Wide Spectrum of Hodgkin and Non-Hodgkin Lymphomas: Implications for CAR T Cell Resistance Younes, S., Libert, D., Zhao, S., Johnsrud, A., Bharadwaj, S., Majzner, R., Frank, M., Miklos, D., Natkunam, Y. SPRINGERNATURE. 2022: 1046-1048
  • Detection of Aberrant CD58 Expression in a Wide Spectrum of Hodgkin and Non-Hodgkin Lymphomas: Implications for CAR T Cell Resistance Younes, S., Libert, D., Zhao, S., Johnsrud, A., Bharadwaj, S., Majzner, R., Frank, M., Miklos, D., Natkunam, Y. SPRINGERNATURE. 2022: 1046-1048
  • Structural Racism is a Mediator of Disparities in Acute Myeloid Leukemia Outcomes. Blood Abraham, I. E., Rauscher, G. H., Patel, A. A., Pearse, W., Rajakumar, P., Burkart, M., Aleem, A., Dave, A., Bharadwaj, S., Paydary, K., Acevedo-Mendez, M., Goparaju, K., Gomez, R., Carlson, K. N., Tsai, S. B., Quigley, J. G., Galvin, J. P., Zia, M., Larson, M. L., Berg, S., Stock, W., Altman, J. K., Khan, I. 1800

    Abstract

    Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic white (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult AML patients from six urban cancer centers and revealed inferior survival among NHB (HR=1.59, 95% CI: 1.15, 2.22) and Hispanic (HR=1.25, 95% CI: 0.88, 1.79) compared to NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across six composite variables: structural racism (census tract disadvantage, affluence and segregation), tumor biology (ELN risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization) and ICU admission during intensive chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, as well as treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.

    View details for DOI 10.1182/blood.2021012830

    View details for PubMedID 35061876

  • Significance of isolated deletion (20q) in donor cells after allogeneic hematopoietic cell transplantation LEUKEMIA & LYMPHOMA Nathan, S., Bharadwaj, S., Luke, K., Kalas, L., Katz, D. A., Hussain, M., Miller, I., Hsu, W., Shammo, J., Venugopal, P., Ustun, C. 2020; 61 (8): 2008-2011
  • Gender and glaucoma: what we know and what we need to know CURRENT OPINION IN OPHTHALMOLOGY Vajaranant, T. S., Nayak, S., Wilensky, J. T., Joslin, C. E. 2010; 21 (2): 91-99

    Abstract

    With growing aging populations and an increase in cases of glaucoma and glaucoma blindness worldwide, aging populations are particularly at higher risk of glaucoma and glaucoma blindness. Awareness of the gender differences might increase attention toward populations at risk.Women not only outlive men, but also outnumber men in glaucoma cases worldwide. Women are at higher risks for angle closure glaucoma, but there is no clear gender predilection for open angle glaucoma. Of interest, there is some evidence suggesting that female sex hormones might be protective of the optic nerve. In addition, it is hypothesized that decreased estrogen exposure is associated with increased risk for open angle glaucoma, yet population-based studies present inconsistent results. Presently, there is insufficient evidence to support hormonal replacement therapy use in glaucoma prevention. In addition, it appears that women carry a larger burden of glaucoma blindness due to longevity and disadvantages in socioeconomic/health beliefs.Current evidence suggests that older women are at risk for glaucoma and glaucoma blindness. Further interdisciplinary research involving investigators, specialized in glaucoma, women's health and health disparities, will lead to better understanding of gender health disparities in glaucoma and better targeting populations at risk.

    View details for DOI 10.1097/ICU.0b013e3283360b7e

    View details for Web of Science ID 000275063500001

    View details for PubMedID 20051857

    View details for PubMedCentralID PMC4326058